Individual cardiomyocyte growth or hypertrophy is a component of the disease process that leads toward heart failure, a disease with a less than 40% 5 year survival rate. Heart failure affects 6 million Americans and is projected to cost the US $30 billion annually. Although current treatments are inadequate, those that blunt hypertrophy improve survival. In order for an adult cardiac muscle cell to grow it must access/unpack and transcribe genes normally expressed during development. This process is dependent upon altering post translational modifications on chromatin i.e. epigenetics. We recently reported that the epigenetic reader protein, BRD4, is necessary for pathologic cardiac hypertrophy in cell culture experiments and animal models of heart failure. BRD4 recruits large protein complexes that stimulate gene expression to areas of the chromatin that have a specific post translational modification (acetylation) on histone proteins. The objectives of this proposal are 1) to understand if this mechanism is also important in other situations where the heart is signaled to grow either by exercise or ischemia 2) investigate how pro-growth signals to the heart muscle are converted into the targeting of BRD4 to pro-growth genes and 3) determine what regulates the amount of BRD4 protein that is present in the heart muscle. These objectives will be met via thoughtful implementation of various experimental techniques including mouse models of exercise induced hypertrophy and coronary artery ligation induced myocardial infarction (ischemia). Additional molecular and biochemical methods will be used to measure mRNA (qPCR) and protein (western blot) expression, assess protein localization within the genome (ChIP), block specific proteins from functioning (pharmacology and genetic knockdown via siRNA), and measure the progression of disease processes (e.g. fibrosis via picosirus red staining). This proposal tests novel and exciting hypotheses regarding mechanisms of cardiomyocyte growth that will advance the fields of epigenetics and cardiology. Moreover, this work will significantly expand the applicant's skill sets in the areas of in vivo cardiovascular physiology, rodent surgery and methods of investigating epigenetic mechanisms which will set the stage for him to transition to a role as independent investigator.